Method for obtaining 5-halogenolaevulinic acid alkyl esters

ABSTRACT

A method for obtaining a 5-bromolevulinic acid methyl ester or a 5-chlorolevulinic acid methyl ester from either a bromination mixture or a chlorination mixture, containing either a 5-bromo-levulinic acid methyl ester or a 5-chlorolevulinic acid methyl ester, respectively, produced by either brominating or chlorinating levulinic acid or a levulinic acid methyl ester, and further including the steps of dissolving the bromination or chlorination mixture in an organic solvent or solvent mixture and cooling the solution, preferably to −20° C.–−40° C., with the 5-bromolevulinic acid methyl ester or 5-chlorolaevulinic acid methyl ester being crystallized out of the solution. The 5-bromolevulinic acid methyl ester or 5-chlorolevulinic acid is then isolated by draining off the solution with the remaining bromination mixture or chlorination mixture, as appropriate.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This is a 371 of PCT/DE02/04302, filed Nov. 22, 2002, and published asWO 03/045895 on Jun. 5, 2003.

The invention relates to a process for obtaining 5-bromo levulinic acidmethyl ester from a bromination mixture, which is obtained bybromination of levulinic acid or levulinic acid methyl ester and whichcontains 5-bromolevulinic acid methyl ester, and to a process forobtaining 5-chlorolevulinic acid alkyl esters.

The bromination of levulinic acid in methanol with one mol equivalent ofbromine yields

-   1. 3-bromolevulinic acid methyl ester-   2. 5-bromolevulinic acid methyl ester-   3. 3,5-bromolevulinic acid methyl ester    and as a result of the consumption of further bromine equivalents    for the formation of 3,5-bromolevulinic acid methyl ester from (1)    and/or (2)-   4. the not brominated levulinic acid methyl ester.

The quantity ratio of the products within the bromination mixturebehaves like (1):(2):(3):(4)=28:56:8:8, whereas insignificant variationsmay occur according to the reaction conditions. In general, however, theselectivity of the formation of the bromination products, especially the5-bromolevulinic acid methyl ester, can not decisively be changed. Thebromination of levulinic acid methyl ester (4) instead of levulinic acidwith one equivalent of bromine in methanol leads approximately to thesame result.

2. Description of the Prior Art

Therefore, the production of 5-bromolevulinic acid methyl ester dependson the mentioned bromination mixture. According to the latestdevelopment of the technology, several processes for the isolation ofthe 5-bromolevulinic acid methyl ester from the bromination mixture areknown.

S. F. McDonald in Can. J. Chem. 1974, 52, 3257–3258 describes a process,from which the mentioned bromine compound is obtained from thebromination mixture by double fractional high vacuo distillation. Inthis way the 5-bromolevulinic acid methyl ester is obtained (relating tothe starting compound levulinic acid) in 30% yield and about 2% of the3,5-dibromolevulinic acid methyl ester as an impurity.

To prevent an acid catalysed change of the ratio of the isomers, thedestination should proceed quickly and the thermal stress of thebromination mixture should be kept as low as possible. A higher thermalstrain particularly has a problematic effect if traces of hydrogenbromide are present, which cause an unfavourable change of the yield tothe disadvantage of the 5-bromolevulinic acid methyl ester. Theexperience also showed, that the amount of the 5-bromolevulinic acidmethyl ester obtained by fractional distillation, considerablydecreases, if small amounts of the 3,5-dibromolevulinic acid methylester are present.

The requirements for the careful production of the desired esterconnected with an optimal yield are met only unsufficiently, since thedouble fractional distillation causes a comparable high expenditure oftime resulting in a high thermal strain of the distillation mixture.

Moreover, if the range of pressure needed for the distillation is notreached within a short period of time, the destination time is lengthendand on top the thermal strain of the bromination mixture increases.

On top of that, it especially has to be considered as a disadvantage,that the separation of the brominated products by distillation accordingto the available process all in all is very expensive, because for thisa double fractional distillation using a vacuum jacketed vigreux columnis necessary. Because of the high technical expense, this process isruled out for a large-scale application.

H.-J. Ha, S.-K. Lee, Y.-J. Ha, J. W. Park, Synth. Comm. 1994, 24(18),2557–2562 describe a process for obtaining 5-bromolevulinic acid methylester, which provides the desired ester from the bromination mixture bymeans of column chromatography. High costs are connected in anunfavourable manner to this process and therefore a purification usingliquid chromatography is out of question when you consider a technicalapplication.

With regard to the use of 5-bromolevulinic acid methyl ester, productionprocesses for the preparation of 5-aminolevulinic acid hydrochloridemust be mentioned in the latest development of the technology.

American patent U.S. Pat. No. 5,907,058 shows a process in which5-aminolevulinic acid hydrochloride is prepared by processing5-bromolevulinic acid methyl ester with sodium diformylamide inwater-free acetonitrile and the following acid catalysed hydrolysis ofthe resulting 5-diformylamino levulinic acid methyl ester.

In the Z. Naturforsch. 1986, 41b, 1593–1594 a process is described by E.Benedikt and H.-P. Köst, which is characterised by the following steps:Processing of 5-bromolevulinic acid methyl ester together with potassiumphthalimide in dimethylforamide yielding 5-phthalimido levulinic acidmethyl ester, which is then hydrolised by an acid.

Finally, in the above mentioned publication of H.-J. Ha, S.-K. Lee,Y.-J. Ha, J. W. Park, Synth. Comm. 1994, 24(18), 2557–2562, a processfor the preparation of 5-aminolevulinic acid hydrochloride is described.This process starts with 5-bromolevulinic acid methyl ester, which isprepared from levulinic acid by bromination, and which is characterisedby the following process steps: Processing of 5-bromolevulinic acidmethyl ester together with sodium azide in dimethyl formamide to5-azidolevulinic acid methyl ester and followed by the catalytichydrogenation and the subsequent ester hydrolysis of the formed5-aminolevulinic acid methyl ester hydrochloride.

The disadvantage of these processes is, that they require the startingmaterial in high purity. The herewith connected high technical expenseand the high costs for the preparation of this product lead to the fact,that a large-scale production of 5-aminolevulinic acid hydrochloridelike mentioned above is unprofitable so far.

SUMMARY OF THE INVENTION

Considering this background, an object of the present invention is toprovide a process for the preparation of 5-bromolevulinic acid methylester, which avoids the mentioned disadvantages, and which allows forthe production of the mentioned substance in high purity and thereforeis suitable for a large-scale application, which leads to acost-effective preparation of the mentioned substance and which,therefore, meets the requirement for a cost-effective preparation of5-aminolevulinic acid methyl ester hydrochloride and 5-aminolevulinicacid hydrochloride. Further, inventive process includes the recycling ofthe resulting undesirable byproducts.

According to the invention the problem is solved by a process, whichintends to use the following process steps:

-   -   dissolving the bromination mixture in an organic solvent or        solvent mixture    -   cooling down the solution to low temperatures, preferably to        temperatures which are lower than −20° C., especially in the        temperature range between −20° C. to −40° C.    -   crystallisation of the 5-bromolevulinic acid methyl ester out of        the solution    -   isolation of the crystalline 5-bromolevulinic acid methyl ester        by draining off the solution with the remaining bromination        mixture.

The suggested process starts from known processes for the preparation of5-bromolevulinic acid methyl ester, which yields a mixture of3-bromolevulinic acid methyl ester, 5-bromolevulinic methyl ester,3,5-bromolevulinic acid methyl ester and levulinic acid methyl ester bymeans of bromination of levulinic acid and levulinic acid methyl ester.

To isolate the 5-bromolevulinic acid methyl ester from a mixtureaccording to the present invention, the mixture will be dissolved in anorganic solvent or solvent mixture first and cooled down in thefollowing process step. During this procedure, temperatures in the rangeof −20° C. and −40° C. must be kept. Thereby, the 5-bromolevulinic acidmethyl ester crystallises in the form of colorless needles or plates,whereas the other parts of the bromination mixture remain in thesolution. To seperate the crystallised ester from the rest of thebromination mixture, the remaining solution is simply drained off.

The basis of the invention is essentially the finding, that the singleparts of the bromination mixture in solution show a completely differentcrystallisation behavior. This behavior proved to be extremelyselective, where in the given temperature range between −20° C. and −40°C. only the 5-bromolevulinic acid methyl ester crystallises. By coolingthe mixture down to this temperatures it is made secure that only thebefore mentioned bromination compound precipitates. The suggestedprocedure shows a yield of 35% to 38% in relation to the quantity oflevulinic acid, whereby the produced bromination product has a highpurity of 99%. Impurities consist after the isolation of the5-bromolevulinic acid methyl ester of levulinic acid methyl ester and3-bromolevulinic acid methyl ester. These two compounds dont't disturbfurther synthesis steps, whereas the 5-bromolevulinic acid methyl estergained according to the procedure of McDonald as mentioned abovecontains 3,5-dibromolevulinic acid methyl ester as an impurity. Thiscompound affects the further reaction steps extremly unfavourable andmakes complicated purification procedures of the final productnecessary! The production process according to the given invention mustbe considered as extremely gentle, since the bromination mixture and theester to be isolated are not exposed to thermal strain by thecrystallisation process. The danger of the acid catalysed change of theratio of the isomers is thus excluded in a favourable manner. Anessential advantage of the procedure according to the invention are itsextremely simple courses in the production of the 5-bromolevulinic acidmethyl ester, which can accordingly be carried out quickly. Thementioned procedure steps may be applied not only in the laboratory butin large-scale installations just in the same. The costs for thetechnical process installations in relation to the produced amount ofthe ester and the production costs are much lower than the correspondingexpenses for the procedure according to the latest development of thetechnology using liquid chromatography or high vacuo distillations.

Several organic solvents or solvent mixtures are suitable for carryingout the selective crystallisation. According to the present inventionare recommended:

the solvents

-   -   ethanol    -   2-propanol    -   diisopropyl ether        or the solvent mixtures    -   diethyl ether plus lower or higher boiling petroleum ether        fractions and/or    -   t-butyl methyl ether plus petroleum ether and/or    -   diethyl ether plus cyclohexane and/or    -   t-butyl methyl ether plus cyclohexane.

In the laboratory experiments mixtures of petroleum ether (30–50° C.)and diethyl ether or tert-butyl methyl ether in a ratio of 1:1 proved tobe reliable. The amount of solvents necessary for the carrying out ofthe process are relatively low.

A further advantage of the procedure according to the invention showswhen the respective byproducts must be disposed of. According to afeature of the invention it is planned to recycle the remainingbromination mixture after the crystallisation of the 5-bromolevulinicacid methyl ester. The remaining mixture contains

-   1. 3-bromolevulinic acid methyl ester-   2. rests of 5-bromolevulinic acid methyl ester-   3. 3,5-bromolevulinic acid methyl ester-   4. and levulinic acid methyl ester.    By this the products 1.–3. can be converted to levulinic acid methyl    ester by catalytic hydrogenation with hydrogen. For this purpose the    mixture is dissolved in methanol and reduced in the presence of a    hydrogenation catalyst by passing in hydrogen at a pressure of 20    bar.

The levulinic acid methyl ester recovered in this way can then be usedas a starting product for the production of the mentioned brominationmixture. For this purpose the levulinic acid methyl ester is dissolvedin methanol and is converted like in the above mentioned bromination oflevulinic acid methyl ester with elemental bromine into the brominationmixture. This conversion nearly yields the same mixture of isomers asthe bromination of levulinic acid. The mixture contains especially5-bromolevulinic acid methyl ester in a high concentration and can so beused with advantage as a starting product for the procedure according tothe invention.

As a catalyst palladium on carbon is suggested according to the giveninvention. The advantage of this catalyst is that it can be regeneratedafter the hydrogenation reaction.

When the hydrogenation of the remaining bromination mixture is madehydrogen bromide is the only byproduct. This product can be disposed ofwithout problems when it is converted to carbon dioxide, water andsodium bromide by sodium hydrogen carbonate. The given invention showsrespective steps for the procedure. A cost-intensive and/or theenvironmentally harmful disposal of byproducts is not necessary at allin the production of 5-bromolevulinic acid methyl ester according to theprocedure invented.

The low-cost production of 5-bromolevulinic acid methyl ester accordingto the given invention opens up a wide range of applicationpossibilities of the given ester. According to the invention especiallythe use for the production of 5-aminolevulinic acid methyl esterhydrochloride and the thereof gained 5-aminolevulinic acid hydrochlorideis intended. The last mentioned compound is used for the cancerdiagnosis and for the therapy of carcinomas as well, especially forbladder cancer carcinomas. On top, 5-aminolevulinic acid hydrochlorideis used as a broad spectrum herbicide in the agricultural sector. Sincethis substance occurs in nature itself, this herbicide has theadvantageous characteristic that it is biodegredable and doesn't provideunnatural and problematic metabolites.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A large-scale production of 5-aminolevulinic acid hydrochloride faileduntil now, inspite of intensive efforts because the costs for theproduction of the starting product were to high. Up to the presentmoment the substance is therefore produced only in small quantitieswhich results in the disadvantage of high prices. One gram of thesubstance costs today on the chemical market about 30 to 50 ∈ and inmedical quality 75 ∈. A broad application of 5-aminolevulinic acidhydrochloride in agriculture is not possible because the prices are tohigh. The low-cost production of 5-bromolevulinic acid methyl esteraccording to the given invention therefore provides the conditions for alarge-scale production of 5-aminolevulinic acid hydrochloride. The useaccording to the invention according to the proposed procedure produced5-bromolevulinic acid methyl ester for the production of5-aminolevulinic acid hydrochloride also contains the use of proceduresdescribed in the latest developments of the technology.

When using 5-bromolevulinic acid methyl ester for the production of5-aminolevulinic acid hydrochloride it is according to the inventionespecially suggested, that the last process step for the production of5-bromolevulinic acid methyl ester is directly connected to the firstprocess step for the production of 5-aminolevulinic acid hydrochloridewithout changing the reaction vessel.

In the usual synthesis of 5-aminolevulinic acid hydrochloride5-bromolevulinic acid methyl ester is a liquid. In this form it showsstrongly lachrymatory and skin irritating properties, every contact withthe substance must therefore be avoided. The crystalline form of thebromination product however shows less irritating features. If theproduct is left in the reaction vessel after crystallisation for thecarrying out of the following processes a contact with people is avoideda priori. The danger of eye and skin irritations is so completelyexcluded.

By the proposed procedure a further advantage is obtained which is basedin the omission of a storing of the 5-bromolevulinic acid methyl esterand the problems connected. The brominated compound tends in thepresence of traces of acid—for example hydrogen bromide—to an acidcatalised isomerisation in the compounds 3-bromo-, 3,5-dibromo- andlevulinic acid methyl ester. It therefore usually requires a carefulstoring, which, however, is excluded in the given procedure.

On top, the two following steps from 5-bromolevulinic acid methyl esterto 5-aminolevulinic acid hydrochloride run at already 20° C. to 25° C.(from time to time even exotherm) so that no energy is required and thereaction mixtures must only be stirred.

In an alternative, preferred embodiment, a further production procedureis mentioned. 5-bromolevulinic acid methyl ester and 5-chlorolevulinicacid esters are starting compounds for the production of thepharmacologically important substance 5-aminolevulinic acidhydrochloride.

According to the latest developments in the technology the production ofthe 5-bromolevulinic acid methyl ester is considered difficult becauseof the cost-intensive work-up of the production mixture by means ofdistillation and chromatography. Hereby, especially the stronglylachrymatory properties of the liquid 5-bromolevulinic acid methyl esterproved to be disadvantageous. The lachrymatory feature is hereby aresult of the bromo methyl ketone moiety in the compound and is valid ingeneral for compounds containing such a moiety as a structural elementin the molecule (comp. for example M. Gaudry, A. Marquet, OrganicSyntheses, Coll. Vol. 6, 193–195).

To exclude the declared disadvantages of the 5-bromo compounds and toproduce more stable, not lachrymatory, storable—at the C-5 positionhalogen substituted derivates—instead of the 5-bromo compounds the5-chloro or 5-iodo compounds are suitable. The 5-chloro compounds don'tpossess lachrymatory properties in comparison to the 5-bromo compounds,because they have a chloro methyl ketone moiety instead of a bromomethyl ketone moiety. On top, they are thermically much more stable incomparison to the bromo compounds and don't tend under the conditions ofthe distillation to acid catalised isomerisations. This feature is alsovalid for other chloro methyl ketones (comp. E. Warnhoff, M. Rampersad,P. S. Raman, F. W. Yerhoff, Tetrahedron Lett. 1978, 19, 1659–1662).

The production of chloro esters of the levulinc acid, which aresubstituted at the C-5 position by direct chlorination of levulinic acidor esters thereof with or without an organic thinner by passing inchlorine gas has the disadvantage that you receive—in comparison to thebromination with elemental bromine—a strongly reduced selectivity of thehalogenation to the disadvantage of the desired 5-chloro compounds. Forexample the chlorination of levulinic acid leads to such a stronglyreduced selectivity that you receive as a main product 3-chlorolevulinic acid. Besides not desired poly chlorination products as3,3-dichloro-, 3,5-dichloro-, 5,5-dichlorolevulinic acid emerge as wellas further unknown products together with the not converted levulinicacid (comp. EP 0397048). In analogy to this you receive substancemixtures approximately corresponding to the above mentioned when you tryto chlorinate levulinic acid esters under the most different conditions.It is very difficult to separate these substance mixtures, the yieldsare bad and they are therefore not usual for further conversions. Whenyou chlorinate levulinic acid ethyl ester without thinners you receivefor example mainly the 3-chlorolevulinic acid ethyl ester. Thechlorination of levulinic acid ethyl ester with sulphuryl chloride in anunpolar organic solvent yields with the reverse selectivity mainly the3-chlorolevulinic acid derivative (comp. EP 0397048).

In EP 58392 a procedure for the production of 5-chlorolevulinic acidethyl ester is described that starts from succinic acid mono ethyl estermono chloride. This compound is converted with diazo methane at −5° C.and is after that worked up by passing in hydrogen chloride. You receiveso the desired compound in pure form and in a high yield but thedifficult handling of explosive diazo methane makes this method for thelarge-scale use not suitable. The same procedure is described in PL136454. Instead of the succinic acid mono ethyl ester mono chloride therespective methyl ester derivative is used and results in the formationof 5-chlorolevulinic acid methyl ester.

The 5-chlorolevulinic acid alkyl esters are starting compounds for theproduction of other substances and are further converted by thenucleophilic substitution of the halogen atom.

Besides alkali imides and alkali azides tertiary amines are suitablenucleophiles. The tertiary amine hexamethylene tetramine(urotropine) isdescribed as a cheap and commercially available nucleophilic reagent forthe introduction of the amino group, for example in bromo methyl ketones(comp. N. Blazevic, D. Kolbah, B. Berlin, V. {hacek over (S)}unjic, F.Kajfez, Synthesis, 1979, 161–176).

The conversion of 5-chlorolevulinic acid methyl ester with urotropineresults in 5-urotropiniumlevulinic methyl ester chloride, a quarternaryammonium salt of the levulinic acid methyl ester that in connection withthis invention has been produced for the first time and directly beenconverted to 5-aminolevulinic acid hydrochloride. In WO 02/32852A2 theproduction of 5-urotropiniumlevulinic esters from 5-bromolevulinic acidesters (chain lengths of the ester alkyl groups C1–C5) and theirconversion to 5-aminolevulinic acid hydrochloride by acid catalysedhydrolysis is described. As a disadvantage of this procedure descriptionyou must consider, that in the final product ammonium chloride andammonium bromide exist as inorganic impurities and the 5-aminolevulinicacid might occur as the hydrochloride as well as the hydrobromide.Ammonium salts as impurities are only difficult to seperate from thefinal product—5-aminolevulinic acid hydrochloride/5-aminolevulinic acidhydrobromide—so the task to gain 5-aminolevulinic acid hydrochloride ina purity necessary for medical purposes might be only difficult to solveaccording to this procedure description.

Behind this background, the procedure proposed for the preparation of5-chlorolevulinic acid alkyl ester is described.

The proposed procedure starts from known procedures for the productionof 5-bromolevulinic acid esters, where by bromination of levulinic acidor levulinic acid methyl ester a mixture of 5-bromo-, 3-bromo-,3,5-dibromo- and the not brominated levulinic acid ester is the result.

The bromination products are extracted with an organic solvent from analcohol/water mixture, which you receive after the work-up of thebromination step with water and the extract is stirred after that attemperatures between 20–25° C. and the boiling temperatures of therespective solvents with sodium chloride or saturated aqueous sodiumchloride, suitably in the presence of an phase-transfer catalyst. Inthis reaction step the bromine atoms in the brominated esters areexchanged by chlorine atoms. This exchange takes place within arelatively short time, in a careful manner and quantitative. The mixtureof chlorolevulinic esters produced here doesn't show any lachrymatoryproperties. The exchange of chlorine and bromine by a halogen in theproduced pure bromolevulinic alkyl esters or chlorolevulinic alkylesters can be made in principal also with fluorine and iodine. Theexchange of chlorine or bromine can under the conditions of thephase-transfer catalysis also be made with the neat bromination mixture.

Non-toxic and harmless ethyl acetate proved to be a very suitableorganic solvent for the bromine/chlorine exchange, which is on topregenerable and can be lead back to the synthesis cycle. As with wateronly with difficulty or not mixable solvents for the phase-transfercatalysed halogen exchange are also suitable:

-   ester like:    -   butylacetate    -   amylacetate-   alcohols like.    -   butanol    -   pentanol    -   isobutanol-   ethers like:    -   di-n-buthyl ether    -   diisopropyl ether    -   diisoamyl ether    -   tert-butyl methyl ether-   aliphatic and aromatic hydrogen halides like (this solvents are only    suitable for the exchange of bromine/chlorine but not for the    bromine or chlorine/iodine or fluorine exchange):    -   dichloromethane    -   tetrachloroethylene    -   tetrachloromethane    -   1,1-dichloroethane.

As phase-transfer catalysts the following quarternary ammonium salts andquarternary phosphonium compounds can be listed as examples:

-   -   tetrabutyl ammonium bromide    -   tetrabutyl ammonium chloride    -   tetrabutyl ammonium iodide    -   benzyltrimethyl ammonium bromide    -   tetrabutyl ammonium hydrogen sulfate    -   benzyldimethyl-n-dodecyl ammonium bromide    -   trioctylmethyl ammonium chloride (adogen 464)    -   ethyltrioctyl phosphonium bromide    -   hexadecyltributyl phosphonium bromide    -   phase-transfer catalysts which bases on polymers.

With regard to the large-scale production of 5-chlorolevulinic acidalkyl esters the decribed process is superior to all previous processes.The proportion of the produced 5-chlorolevulinic acid alkyl ester in themixture is equal or higher than 56%. Byproducts are merely3-chlorolevulinic acid esters (<28%), the 3,5-dichlorolevulinic acidesters (about 8%) and the not converted levulinic acid esters (about8%).

While doing this the bromination step and the following bromine/chlorineexchange are carried out without changing the reaction vessel.

After the drying and distillation off of the solvent from thechlorination mixtures the residue is purified by means of fractionaldistillation. In comparison with the brominated products thecorresponding chlorinated products have essentially lower boilingpoints. The 3-chlorolevulinic esters together with the not convertedlevulinic acid esters always form the first fraction of the distillationfollowed by the 5-chlorolevulinic esters in the second fraction. Thehigher chlorinated products have a higher boiling point compared withthe mono-chlorinated products and form the third fraction. The massbalance sheet of the distillate in relation to the starting distillationgood is always >90%. The fractional distillation is carried out invacuo, which according to the present invention means, that it is workedwith a negative pressure. The yield (in relation to the startingquantity of levulinic acid or levulinic acid methyl ester) of5-chlorolevulinic acid methyl ester after the distillation is at least50% (purity>98%).

On the one hand the sequence of the halogenation reactions takes intoconsideration, that the bromination of the starting compound is moreselective than their chlorination. On the other hand the mixture of thechlorinated levulinic acid compounds, which is present after thequantitative halogen exchange, behaves in comparison to the presentbromination mixture more stable towards acid catalysed isomerisationbecause the chlorination products have clearly lower boiling points andtherefore the activation of a thermal caused production of hydrogenchloride from the 3,5-dichloro compound is avoided.

In view of a synthesis of the 5-aminolevulinic acid hydrochloridestarting from 5-chlorolevulinic acid methylester there is in comparisonwith the homologue bromine compound an essential advantage, that youproduce only sodium chloride as an inorganic by-product when it isconverted with sodium azide or other nitrogen nucleophiles, which areused as their sodium salts (for example imides). In organic solventssodium chloride is practically unsolulable. That means, that thisby-product may be removed in a simple manner by filtration and theproduced product may be lead directly to the following step practicallywithout the presence of any inorganic impurity. In view of the use of5-aminolevulinic acid hydrochloride in the medical field this fact is inso far of great importance as in the so produced product only sodiumchloride and no other inorganic impurities can be present, which forexample in the case of the present sodium chloride would cause a moreexpensive analytics.

In connection with this it is remarkable, that the 5-chlorolevulinicacid methyl ester can be also selectively produced by means of lowtemperature crystallisation from the chlorination mixture, which you getfrom the bromination mixture of levulinic acid or levulinic acid methylester in methanol and the subsequent bromine/chlorine exchange, in agentle manner as already described for the 5-bromolevulinic acid methylester. As in the case of the 5-bromolevulinic methyl ester you proceedin the same way by using the same solvents and solvent mixtures andtemperatures between −20° C. and −40° C. You get the 5-chlorolevulinicacid methyl ester in 35–38% yield and >98 purity. Impurities are the3-chlorolevulinic acid methyl ester and the unconverted levulinic acidmethyl ester. The 5-chlorolevulinic acid esters of the alcohols withchain lengths of C2–C4 can not be produced by low-temperaturecrystallisation because no crystallisation occurs under theseconditions. The same is valid for the corresponding bromination mixturesof the 5-bromolevulinic acid esters which are produced from alcoholswith chain lengths of C2–C4.

The first fraction of the distillation always consists of small amountsof the 5-chlorolevulinic acid ester, the 3-chlorolevulinic acid esterand the unconverted levulinic acid ester. These compounds can beconverted in the levulinic acid esters by catalytic hydrogenation in thepresence of an hydrogenation catalyst and a non-nucleophilic tertiaryamine (for the purpose of catching the generated hydrogen chloride) andcan therefore be quantitatively lead back to the bromination step. Theused hydrogenation catalyst, preferably palladium on carbon according tothe invention, may be regenerated. As solvent suitably the respectivealcohol is used, which forms the rest of the ester. Only aminehydrochloride is formed as by-product The used solvents are regenerable.The catalytic hydrogenation of the by-products yields the levulinic acidesters and opens a possibility to regenerate the starting materials andto lead them back into the synthesis cycle. Alternatively, the 3-chlorocompounds can be transferred into other synthetic pathways, so that acost-intensive disposal of the byproducts can be avoided. The solventsand the catalyst are regenerable, only the hydrochloride of a tertiaryamine has to be disposed of. The synthesis starts with cheap levulinicacid or the esters thereof, which are available in large quantities onthe market and which can be produced on a large scale, for example fromwaste paper (comp. E. S. Oson, M. R. Kjelden, A. J. Schlag, R. K.Shamma, ACS Symposium Series 2001, 784, 51–63). The 5-chlorolevulinicacid esters which contain ester alkyl groups>C2 can be producedunproblematically and in nearly quantitative yield by means oftransesterification of the 5-chlorolevulinic methyl- and ethyl esterusing the concerning alcohols according to standard procedures. The5-chlorolevulinic acid can be produced by means of ester hydrolysis ofthe 5-chloro levulinic esters according to standard procedures in a highyield.

EXAMPLES

Further details, features and advantages of the present invention can bedrawn from the following part of the description. In this part of thedescription examples are described, which were carried out in thelaboratory.

EXAMPLE 1 Preparation of 5-bromolevulinic Acid Methyl Ester fromLevulinic Acid

In a threee-necked flask equipped with a mechanical stirrer, a refluxcondenser, an internal thermometer and a dropping funnel, to a solutionof levulinic acid (600 g, 5.17 mol) in 2400 ml bulk grade methanolbromine (826.2 g, 5.17 mol) was dropped at 20–25° C. during 15 min.Within 1.5 h the reaction temperature rised to 60° C. Afterwards, thecolor of the solution changed from dark-red to orange within 2 min. Atthis time the reaction was finished (¹H-NMR control). Water was added(2500 ml), which caused the precipitation of a yellowish oil. The oilwas separated and the remaining solution was extracted withdichloromethane (3×300 ml). The combined organic extracts were combinedwith the oil and the resulting mixture was washed with saturated aqueoussodium hydrogen carbonate (3×200 ml) and saturated aqueous sodiumchloride (3×200 ml). Drying of the organic layer with Na₂SO₄ anddistillation of the solvent in vacuo yielded a pale yellow oilconsisting of 3-bromolevulinic acid methyl ester (1) (28%),5-bromolevulinic acid methyl ester (2) (56%), 3,5-dibromolevulinic acidmethyl ester (3) (8%) and levulinic acid methyl ester (4) (8%). Thecomposition of the resulting product mixture was monitored by theNMR-spectrum, and the product ratio was calculated from the sum of theintegrations of the 5-CH₂ (2, 3) and the 5-CH₃ (1, 4) signals of thecompounds, whereas the sum of the single proton integrations was set to100%.

Diethyl ether, t-butyl methyl ether and trichloromethane are alsosuitable organic solvents for the isolation of the products by means ofextraction. Best results were otained by the use of trichloromethane,dichloromethane and ethyl acetate.

Diethyl ether/petroleum ether (30–50° C.) 1:1 (4000 ml) was added to themixture. The resulting solution was cooled down to temperatures between−20 and −40° C. for 2 h while colorless needles or plates crystallisedout of the solution. Removal of the mother liquor, subsequent swirlingof the remaining crystals with precooled (−20° C.) diethylether/petroleum ether (30–50° C.) 1:1 (1000 ml) and removal of thesolution yielded 5-bromo levulinic acid methyl ester (400 g, 37%) ascolorless crystals, m. p. 12–15° C.

Ethanol, 2-propanol, diisopropyl ether and t-butyl methylether/petroleum ether (30–50° C.) 1:1 are also suitable solvents for thepreparation of pure 5-bromo levulinic acid methyl ester by means oflow-temperature crystallisation. Cyclohexane and the higher-boilingpetroleum ether fractions instead of the low-boiling petroleum etherfractions in combination with the ethers mentioned above may also beused as solvents for the purpose of crystallisation. The best resultswere obtained by using the solvent mixture described according toExample 1.

EXAMPLE 2 Preparation of 5-bromolevulinic Acid Methyl Ester fromLevulinic Acid Methyl Ester

In a threee-necked flask equipped with a mechanical stirrer, a refluxcondenser, an internal thermometer and a dropping funnel, to a mixtureof levulinic acid methyl ester (5 g, 38.4 mmol) and bulk grade methanol(30 ml) bromine (6.14 g, 38.4 mmol) was dropped at 20–25° C. during 15min. Stirring was continued at 20–25° C. After 1.5 h the reactiontemperature rised to 35° C. and the color of the solution changed fromdark-red to orange within 2 min followed by the decrease of the innertemperature to 20–25° C. At this time the reaction was finished. Waterwas added (100 ml), which caused the precipitation of a yellowish oil.The oil was separated and the remaining aqueous solution was extractedwith dichloromethane (2×30 ml). The combined organic extracts were addedto the oil and the resulting mixture was washed with saturated aqueoussodium hydrogen carbonate (2×20 ml) and saturated aqueous sodiumchloride (2×20 ml). Drying of the organic layer with Na₂SO₄ anddistillation of the solvent in vacuo yielded a pale yellow oil (7.56 g)consisting of 3-bromolevulinic acid methyl ester (1) (28%),5-bromolevulinic acid methyl ester (2) (56%), 3,5-dibromolevulinic acidmethyl ester (3) (8%) and levulinic acid methyl ester (4) (8%). Diethylether/petroleum ether (30–50° C.) 1:1 (50 ml) was added to the mixture.The resulting solution was then cooled down to temperatures between −20and −40° C., and within 2 h colorless needles or plates crystallised outof the solution. Removal of the mother liquor, subsequent swirling ofthe remaining crystals with precooled (−20° C.) diethyl ether/petroleumether (30–50° C.) 1:1 (20 ml) and removal of the solution yielded5-bromolevulinic acid methyl ester (2.9 g, 36%) as colorless crystals,m. p. 12–15° C.

EXAMPLE 3 Preparation of Levulinic Acid Methyl Ester from the RemainingMother Liquors, Which were Obtained by Low-Temperature Crystallisationof 5-bromolevulinic Acid Methyl Ester According to Example 1, Consistingof 3-bromolevulinic Acid Methyl Ester, 5-bromolevulinic Acid MethylEster, 3,5-dibromolevulinic Acid Methyl Ester and Levulinic Acid MethylEster

Distillation of the solvent from the combined mother liquors obtainedfrom the low-temperature crystallisation of 5-bromolevulinic acid methylester according to Example 1 in vacuo afforded a mixture consisting of3-bromolevulinic acid methyl ester (61%), 5-bromolevulinic acid methylester (23%), 3,5-dibromolevulinic acid methyl ester (8%) and levulinicacid methyl ester (8%). The mixture (5 g) was dissolved in bulk grademethanol (20 ml), a hydrogen catalyst (palladium on carbon) was thenadded and the mixture was hydrogenated for 5 h while passing in hydrogenat a pressure of 20 bar at 20–25° C. By monitoring the hydrogenation, itwas found that the reaction was completed after 5 h (¹H-NMR, ¹³C-NMR)and besides hydrogen bromide only levulinic acid methyl ester has beenformed. Water was added (20 ml) and the resulting mixture was extractedwith dichloro methane (3×20 ml). The combined organic extracts werewashed with saturated aqueous sodium hydrogen carbonate (3×10 ml) andsaturated aqueous sodium chloride. Drying of the organic layer withNa₂SO₄, followed by distillation of the solvent in vacuo yielded 2.5 g(80%) levulinic acid methyl ester. The obtained product may be used forthe preparation of 5-bromolevulinic acid methyl ester according toExample 2. The further purification of the obtained levulinic acidmethyl ester by distillation is not necessary, so that the raw-productmay be directly lead back to the bromination step after removing thehydrogen bromide for the most part.

EXAMPLE 4 Preparation of 5-chlorolevulinic Acid Methyl Ester,5-chlorolevulinic Acid Ethyl Ester, 5-chlorolevulinic Acid Propyl Esterand 5-chlorolevulinic Acid n-butyl Ester from Bromination Mixtures ofthe Corresponding Bromination Products by Phase-transfer CatalysedBromine/chlorine Exchange. General Method for the Preparation of the5-chlorolevulinic Acid methyl-, -ethyl-, -propyl- and -n-butyl Esters

In a threee-necked flask equipped with a mechanical stirrer, a refluxcondenser, an internal thermometer and a dropping funnel, to apre-cooled solution (10° C.) of levulinic acid (1 mol) or levulinic acidmethyl ester (1 mol) and the corresponding alcohol (400 ml) which formsthe alkyl chain of the prepared ester, bromine (1 mol) was added.Stirring was continued until the initial color of the mixture changedfrom dark-red to orange or yellow. While stirring, the mixture wasallowed to attain 20–25° C. The reaction was finished whendecolorisation of the mixture occured. Water was added (400 ml) whichcaused precipitation of an oil. The oil was separated and the remainingaqueous solution was extracted with a total of 200 ml of ethyl acetate.The aqueous layer was separated and to the organic layer were addedsaturated aqueous sodium chloride (1000 ml) and trioctyl methy ammoniumchloride (10 g). Stirring was continued at 20–25° C. or under refluxuntil the reaction was virtually complete (DC, ¹H-NMR). If necessary,the aqueous sodium chloride was replaced by a freshly prepared solution.The organic layer was separated, washed with water (100 ml), dried withNa₂SO₄, and subsequently the solvent was distilled in vacuo. In aclaisen apparatus, the residue was distilled in vacuo (10 mm, except the5-chlorolevulinic acid n-butyl ether, b.p. 158° C. at 10 mm). In allcases a first fraction was taken, which contained the unconvertedlevulinic acid alkyl ester, the 3-chlorolevulinic acid alkyl ester andsmall amounts of the desired 5-chlorolevulinic acid alkyl ester. Theresidue of the distillation consisted of small amounts of both5-chlorolevulinic acid alkyl ester and 3,5-dichlorolevulinic acid alkylester.

Differing from the general method, the 5-chlorolevulinic acid n-butylester was prepared by washing the bromination mixture acid-free withwater. The resulting solution of the bromination mixture in n-butanolwas supplied to the bromine/chlorine exchange step by phase-transfercatalysis. Afterwards, the process was continued as described accordingto the general method. The distillation was carried out at 5·10⁻² mm.

EXAMPLE 5

Preparation of 5-chlorolevulinic acid methyl ester from a mixture of3-chloro-, 5-chloro-, 3,5-dichlorolevulinic acid ethyl ester andlevulinic acid methyl ester consisting of the same product ratio, whichis obtained by the bromination of both levulinic acid and levulinic acidmethyl ester according to the Examples 1 and 2.

According to Example 4, a chlorination mixture of levulinic acid methylester was prepared. After the work-up as described, the solvent wasdistilled in vacuo. The product ratio of 5-chlorolevulinic acid methylester: 3,5-dichlorolevulinic acid methyl ester:3-chlorolevulinic acidmethyl ester:levulinic acid methyl ester agreed with that found for thecorresponding bromination products according to Example 1 and wascalculated by means of the integration of the characteristic NMR protonsignals.

Diethyl ether/petroleum ether (30–50° C.) 1:1 (800 ml) was added to themixture of the raw-products and the mixture was kept at temperaturesbetween −20° C. and −40° C. for 4 h while the desired productcrystallised out of the solution as colorless needles. Removal of themother liquor, subsequent swirling of the remaining crystals withpre-cooled (−20° C.) diethyl ether/petroleum ether (30–50° C.) 1:1 (200ml) and removal of the solution yielded 5-chlorolevulinic acid methylester (62 g, 38%) as colorless crystals, m. p. 8–13° C. Thecrystallisation may also occur successfully using the additional listedsolvents described in Example 1.

The NMR data of the product agree with the data of the 5-chlorolevulinicacid methyl ester obtained according to Example 4. The product, which isprepared by this method is obtained in >98% purity.

EXAMPLE 6 Catalytic Hydrogenation of the Residue of the Low-TemperatureCrystallisation According to Example 5—Recycling of the Levulinic AcidMethyl Ester

Distillation of the solvent from the combined mother liquors obtainedfrom the low-temperature crystallisation of 5-bromo levulinic acidmethyl ester according to Example 1 in vacuo afforded a mixtureconsisting of 3-bromolevulinic acid methyl ester (61%), 5-bromolevulinicacid methyl ester (23%), 3,5-dibromolevulinic acid methyl ester (8%) andlevulinic acid methyl ester (8%). The mixture (5 g) was dissolved inbulk grade methanol (20 ml), a hydrogen catalyst (palladium on carbon)and 2.45 g of triethyl amine were added and the mixture was hydrogenatedfor 5 h while passing in hydrogen at a pressure of 20 bar at 20–25° C.The reaction was completed after 5 h (¹H-NMR). The catalyst was thenfiltered off from the reaction mixture, and after the distillation ofthe solvent in vacuo, ethyl acetate was added and the solid was filteredoff. Distillation of the sovent and the residue in vacuo afforded 2.96 g(95%) levulinic acid methyl ester.

EXAMPLE 7 Examplary Transesterification of 5-chlorolevulinic Acid MethylEster with 1-propanol

To a solution of 5-chlorolevulinic acid methyl ester (10 g) in1-propanol (50 ml) and concentrated sulfuric acid was added (0.5 ml) andthe reaction mixture was refluxed for 3 h. Thereafter, the methanol andthe excess 1-propanol were distilled in vacuo. Dichloromethane was addedto the residue and the organic layer was washed with saturated aqueoussodium hydrogen carbonate and water. Drying of the organic layer withNa₂SO₄ followed by distillation of the solvent in vacuo yielded 5.4 g(quant.) 5-chlorolevulinic acid propyl ester. The NMR data agreed withthe data for the product obtained according to Example 4.

EXAMPLE 8

Examplary conversion of the 5-chlorolevulinic acid alkyl esters withsodium azide to the 5-azidolevulinic acid alkyl esters. General methodfor the preparation of the 5-azido levulinic acid methyl-, -ethyl-,-propyl- and n-butyl esters.

The 5-chlorolevulinic acid alkyl esters (1 g) were dissoled in bulkgrade acetone (3 ml), the stoechiometric amount of sodium azide wasadded and the reaction mixture was stirred at 20–25° C. for 10 h.Filtration of the separated sodium chloride from the reaction mixtureand distillation of the solvent in vacuo afforded the desired5-azidolevulinic acid alkyl esters as yellow to dark-yellow oils inquantitative yield (purity>99%). No byproducts were formed.

EXAMPLE 9

Examplary conversion of 5-aminolevulinic acid hydrochloride by catalyticreduction of the 5-azidolevulinic acid alkyl esters and subsequenthydrolysis of the intermediate 5-aminolevulinic acid alkyl esterhydrochlorides. General method for the preparation and the hydrolysis ofthe intermediate 5-aminolevulinic acid alkyl ester hydrochlorides, whichcontain ester alkyl chains C1–C3 by catalytic hydrogenation of the alkylesters and subsequent acid catalysed hydrolysis with formation of5-aminolevulinic acid hydrochloride.

5-Azidolevulinic acid alkyl ester (1 g) was dissolved in a mixture ofthe alcohol (10 ml), which represents the alkyl chain in the final esterand aqueous hydrochloric acid (2 mol/l). A hydrogenation catalyst(palladium on carbon) was added and the mixture was hydrogenated for 3 hwhile passing in hydrogen at a pressure of 1–6 bar. By monitoring thehydrogenation, it was found that the hydrogenation was completedquantitatively after 3 h (¹H-NMR). The hydrogenation is accompanied byan increase of the reaction temperature to 35° C. The reaction iscomplete, when the reaction temperature reaches 20–25° C. again(¹H-NMR). The catalyst was then filtered off from the reaction mixture,and the alcohol was distilled in vacuo. A small amount of activatedcharcoal and aqueous hydrochloric acid (10 ml, 6 mol/l) were added andsubsequently the reaction mixture was refluxed for 5 h. The activatedcharcoal was then filtered off, and both the water and the alcohol wereremoved by distillation in vacuo. While stirring, to the nearlycolorless and viscous residue 2-propanol (20 ml) was added. After oneminute a white and crystalline solid abruptly precipitated. The solidwas filtered off using a glass frit Washing of the solid with little2-propanol and drying of the crystals in vacuo yielded colorlesscrystals (85–90%, m. p. 150–151° C.) consisting of pure 5-aminolevulinicacid hydrochloride

When the batch size was increased starting from 75 g of 5-azidolevulinicacid alkyl ester the same result was obtained. The physical andspectroscopical data agree with those found in the literature (H.-J. Ha,S.-K. Lee, Y.-J. Ha, J. W. Park, Synth. Comm. 1994, 24(18), 2557–2562).

EXAMPLE 10

Examplary reaction of 5-chlorolevulinic acid alkyl esters withhexamethylene tetramine (urotropine) to the corresponding5-urotropiniumlevulinic acid alkyl esters. Subsequent acid catalysedhydrolysis of the 5-urotropiniumlevulinic acid alkyl esters resulting inthe formation of 5-amino levulinic acid hydrochloride.

5-Chlorolevulinic acid alkyl ester (5 g) was dissolved in ethanol (50ml) and the calculated stoechiometric amount of hexamethylenetetramine(urotropine) was added. Afterwards, the reaction mixture wasrefluxed for 2 h. Filtration of the precipitated ammonium chloride andevaporation of the alcohol and the volatile formaldehyde diacetale invacuo afforded a yellow to brown residue. The residue was dissolved inmethanol and subsequently, the 5-aminolevulinic acid hydrochloride wasprecipitated as a white and microcrystalline solid by addition ofdiethyl ether. Filtration and subsequent drying of the solid in vacuoyielded pure 5-aminolevulinic acid hydrochloride (75–85%, m p. 150–151°C.). The NMR data of the obtained product agree with those found in theliterature (H.-J. Ha, S.-K. Lee, Y.-J. Ha, J. W. Park, Synth. Comm.1994, 24(18), 2557–2562).

1. A method for obtaining 5-bromo-levulinic acid methyl ester,comprising the steps of: brominating a member selected from the groupconsisting of levulinic acid, levulinic acid methyl ester and acombination thereof, for producing a bromination mixture containing a5-bromolevulinic acid methyl ester; dissolving said bromination mixturein an organic solvent or solvent mixture for forming a solution; coolingsaid solution for crystallizing 5-bromolevulinic acid methyl ester fromsaid solution and obtaining crystalline 5-bromolevulinic acid methylester; wherein said cooling step is carried out at a temperature lowerthan −20° C. and, draining off said solution with any remaining saidbromination mixture for isolating said crystallizing 5-bromolevulinicacid methyl ester, thereby obtaining 5-bromolevulinic acid methyl ester.2. The method for obtaining 5-bromo-levulinic acid methyl esteraccording to claim 1, wherein said organic solvent used in said step ofdissolving said bromination mixture is a member selected from the groupconsisting of ethanol, 2-propanol, diisopropyl ether and a combinationthereof.
 3. The method for obtaining 5-bromo-levulinic acid methyl esteraccording to claim 1, wherein said solvent mixture used in said step ofdissolving said bromination mixture is a member selected from the groupconsisting of diethyl either with petroleum ether fractions, t-butylmethyl either with petroleum ether, diethyl ether with cyclohexane,t-butyl methyl either with cyclohexane and a combination thereof.
 4. Themethod for obtaining 5-bromo-levulinic acid methyl ester according toclaim 1, further comprising the steps of: catalytic hydrogenating theremaining said bromination mixture to levulinic acid methyl ester; and,brominating said levulinic acid methyl ester for obtaining additionalsaid bromination mixture containing 5-bromolevulinic acid methyl ester.5. The method for obtaining 5-bromo-levulinic acid methyl esteraccording to claim 4, wherein palladium on carbon as a catalyst in saidstep of catalytic hydrogenating.
 6. The method for obtaining5-bromo-levulinic acid methyl ester according to claim 1, wherein saidcooling step is carried out at a temperature between −20° C. to −40° C.7. A method for obtaining 5-chloro-levulinic acid methyl ester,comprising the steps of: chlorinating a member selected from the groupconsisting of levulinic acid, levulinic acid methyl ester and acombination thereof, for producing a chlorination mixture containing a5-chlorolevulinic acid methyl ester; dissolving said chlorinationmixture in an organic solvent or solvent mixture for forming a solution;cooling said solution for crystallizing 5-chlorolevulinic acid methylester from said solution and obtaining crystalline 5-chlorolevulinicacid methyl ester; and, draining off said solution with any remainingsaid chlorination mixture for isolating said crystallizing5-chlorolevulinic acid methyl ester, thereby obtaining 5-chlorolevulinicacid methyl ester.
 8. The method for obtaining 5-chloro-levulinic acidmethyl ester according to claim 7, wherein said organic solvent used insaid step of dissolving said chlorination mixture is a member selectedfrom the group consisting of ethanol, 2-propanol, diisopropyl ether anda combination thereof.
 9. The method for obtaining 5-chloro-levulinicacid methyl ester according to claim 7, wherein said solvent mixtureused in said step of dissolving said chlorination mixture is a memberselected from the group consisting of diethyl either with petroleumether fractions, t-butyl methyl either with petroleum ether, diethylether with cyclohexane, t-butyl methyl either with cyclohexane and acombination thereof.
 10. The method for obtaining 5-chloro-levulinicacid methyl ester according to claim 7, further comprising the steps of:catalytic hydrogenating the remaining said chlorination mixture tolevulinic acid methyl ester; and, chlorinating said levulinic acidmethyl ester for obtaining additional said chlorination mixturecontaining 5-chloro-levulinic acid methyl ester.
 11. The method forobtaining 5-chloro-levulinic acid methyl ester according to claim 10,wherein palladium on carbon as a catalyst in said step of catalytichydrogenating.
 12. The method for obtaining 5-chloro-levulinic acidmethyl ester according to claim 7, wherein said cooling step is carriedout at a temperature lower than −20° C.
 13. The method for obtaining5-chloro-levulinic acid methyl ester according to claim 7, wherein saidcooling step is carried out at a temperature between −20° C. to −40° C.14. A method for obtaining 5-chlorolevulinic acid alkyl ester from abromination mixture containing 5-bromolevulinic acid alkyl ester,comprising the steps of: brominating a member selected from the groupconsisting of levulinic acid, levulinic acid methyl ester and acombination thereof, for forming a bromination mixture containing5-bromolevulinic acid alkyl ester; halide exchanging via aphase-transfer catalyzed reaction of said bromination mixture with analkali chloride for obtaining a mixture containing 5-chlorolevulinicacid alkyl ester; and, isolating a 5-chlorolevulinic acid alkyl esterfrom said mixture containing said 5-chlorolevulinic acid alkyl ester viafractional distillation in vacuo.
 15. The method for obtaining5-chlorolevulinic acid alkyl ester from a bromination mixture containing5-bromolevulinic acid alkyl ester according to claim 14, wherein said5-bromolevulinic acid alkyl ester is member selected from the groupconsisting of 5-bromolevulinic acid methyl ester, 5-bromolevulinic acidethyl ester and a combination thereof.
 16. The method for obtaining5-chlorolevulinic acid alkyl ester from a bromination mixture containing5-bromolevulinic acid alkyl ester according to claim 14, whereintrioctylmethyl ammonium chloride is used as a catalyst for saidphase-transfer catalyzed reaction of said halide exchanging step.